In 1747 Isaac de Costa, a Sephardic Jew born in London, arrived in Charleston, South Carolina, where he established himself as a merchant, shipping-agent, and slave-trader, who built a considerable fortune bringing hundreds of black slaves overseas from Africa. Isaac da Costa had been initiated into Freemasonry and appointed a Masonic Deputy Inspector General by fellow Jew Moses Michael Hayes and went on to establish the Sublime Grand Masonic Lodge of Perfection in Charleston prior to his death in 1783.

In 1756 Moses Lindo, a Sephardic Jew born in London in 1712, arrived in Charleston, South Carolina, where he established himself as a slave-owning planter and merchant in the cochineal and indigo trade with London. Lindo imported 49 slaves from Barbados to his South Carolina plantation in the 1750s. At one point in his career he ran an advertisement in the South Carolina Gazette stating that: "If any person is willing to part with a plantation of 500 acres with 60 or 70 Negroes, I am ready to purchase it for ready money." In 1762 he was appointed "Surveyor and Inspector-General of Indigo, Drugs, and Dyes."

Also arriving in Charleston, South Carolina, in 1756, was Moses Lindo's twenty year old indentured servant, Jonas Phillips, who had been born Jonah Feibush in Frankfurt, Germany. After serving his term of indenture, Phillips moved first to Albany, New York in 1759, and then to New York City, where he became a merchant and dealer in slaves. By 1760 Phillips had joined the New York Lodge of Freemasons, and served as shohet (ritual slaughterer) and bodek (examiner of meat) for Shearith Israel. Settling in Philadelphia just before the American Revolution, Phillips was a staunch advocate of the Non-Importation Agreement, and by the beginning of the Revolutionary War he supported the cause of American Independence and in 1778 he enlisted in the Philadelphia militia. By the year 1782 was the second wealthiest Jew in the city. He and his wife Rebecca Mendes Machado maintained their South Carolina ties through several of their 21 children.

In 1757 Isaac Monsanto, a Sephardic Jew born in the Netherlands arrives in New Orleans by way of Curacao establishing himself as a merchant and engaging in the business of shipping slaves and cargo from the Caribbean to the Gulf of Mexico. In 1767 Monsanto purchased a plantation known as Trianon outside of New Orleans. By the time the second Spanish governor took control in 1769, expelling the Jews from Louisiana, Isaac Monsanto had become one of New Orleans' wealthiest merchants. Under Spanish rule, Monsanto was stripped of his holdings and forced to leave the territory, relocating to the town of Mancha near Lake Pontchartrain in British territory, where he was joined by his brothers, Manuel, Jacob and Benjamin; while their sisters relocated to Pensacola, then part of British West Florida. Following Isaac's death in 1778, Manuel, Jacob and Benjamin Monsanto continued to manage their mercantile firm, dealing not only in dry goods but in real estate, commodities, debt collection and slaves. Records show that Benjamin Monsanto traded thirteen slaves for some three thousand pounds of indigo in 1785. By 1790, Manuel and Jacob had set up shop on Toulouse Street in New Orleans, while Benjamin and his wife Clara moved to a 500 acre plantation worked by eleven slaves on St Catherine's Creek near Natchez, Mississippi, where he continued operating part of the family business until his death in 1794. The Monsanto chemical corporation was founded by John Francis Queeny, who married Olga Mendez Monsanto, daughter of Emmanuel Mendes de Monsanto, a descendant of this family.

Among the founders of Richmond, Virginia's Jewish community were men such as Israel and Jacob I. Cohen, Samuel Myers, Jacob Modecai, Solomon Jacobs, Joseph Marx, Zalma Rehine and Baruch and Manuel Judah, all slave holders. Following the Revolutionary War, Richmond was a town of some 2000 people, half of whom were slaves. By 1788, 17% of the White population were Jews and all but one of the Jewish householders held at least one slave as a domestic servant, with one Jewish family owning three. According to Jewish historian, Jacob Rader Marcus, by 1820 "over 75 percent of all Jewish families in Charleston, Richmond, and Savannah owned slaves, employed as domestic servants; almost 40 percent of all Jewish households in the United States owned one slave or more" (United States Jewry, 1776-1985, pg. 585).